Doubly stereoconvergent crystallization enabled by asymmetric catalysis

• Published in: Science (American Association for the Advancement of Science) Vol. 376; no. 6598; pp. 1224 - 1230
• Main Authors: de Jesús Cruz, Pedro, Cassels, William R, Chen, Chun-Hsing, Johnson, Jeffrey S
• Format: Journal Article
• Language: English
• Published: United States 10-06-2022
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abo5048

Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and development of a catalyst-mediated asymmetric Michael addition/crystallization-induced diastereomer transformation of broad scope. The sequence controls three stereogenic centers, two of which are stereochemically labile. The configurational instability of 1,3-dicarbonyls and nitroalkanes, typically considered a liability in stereoselective synthesis, is productively leveraged by merging enantioselective Brønsted base organocatalysis and thermodynamic stereocontrol using a single convergent crystallization. The synthesis of useful γ-nitro β-keto amides containing three contiguous stereogenic centers is thus achieved from Michael acceptors containing two prochiral centers.